Recent Patents on Anti-Infective Drug Discovery - Volume 1, Issue 3, 2006

Chemokines play key roles in inflammatory and immune responses mediated by their respective target cell populations. For instance, release of chemokines from inflammatory cells is a crucial step in the recruitment of cells needed to establish local inflammatory responses (e.g. rheumatoid arthritis). Moreover, recent advances in our understanding of the pathogenesis of human immunodeficiency virus (HIV) infection have revealed that chemokines and chemokine receptors are crucially involved in the molecular mechanism of HIV entry into target cells. Studies have shown that the chemokine receptor CCR5 serves as a critical coreceptor during the viral entry stage of HIV infection, while its ligands macrophage inflammatory protein (MIP)-1α and β and RANTES act as endogenous inhibitors of HIV infection. This makes chemokine/chemokine receptor systems an attractive potential target for the development highly specific drugs with which to improve the management of HIV. This review will discuss the latest developments in the research on chemokine/chemokine receptor systems, especially MIP-1 and CCR5, with a particular focus on their role in the mechanism of HIV infection and on the development of effective therapies against acquired immunodeficiency syndrome (AIDS).

Listeria monocytogenes is a Gram-positive intracellular bacterium that has accounted for a significant proportion of human foodborne infections in recent decades. Although infection with sublethal level of L. monocytogenes generates enduring immunity, it is impractical to apply intact virulent strains as vaccine. Through use of killed, attenuated, naturally avirulent, subcellular and DNA vaccine preparations, significant protection has been achieved in experimental animals against listeriosis. Being a robust bacterium capable of eliciting all aspects of cell-mediated immunity, L. monocytogenes has the potential to become an ideal vector for vaccine delivery against other infective agents. Furthermore, with a high safety threshold, L. monocytogenes has increasingly been recognized as a vaccine vector of choice for a range of bacterial, viral and parasitic pathogens. Not surprisingly, a large number of patents have been filed in recent years that exploit attenuated or naturally avirulent L. monocytogenes strains or its listeriolysin (LLO) protein to enhance specific T cell response in the vaccine recipients or to direct vaccine molecule to the cytoplasm of host cells. Following a brief review on the key features of L. monocytogenes infection and host immune responses to listeriosis, this article summarizes the current state and recent progresses in the Listeria-based vaccine strategies that have been developed against bacterial, viral and parasitic diseases, together with a discussion on the future development trends in the utilization of L. monocytogenes as vaccine vector.

Vaccine discovery stands out as one of the public health interventions that has achieved the greatest impact in world's health. Vaccination is the most effective means of disease prevention, especially for viral infections. Starting with the use of smallpox vaccine by Jenner in the late 1700s, the technology for vaccine development has seen numerous advances. Currently, vaccines available for human viral illness are based on live attenuated (e.g. measles, mumps, and rubella), inactivated (e.g. hepatitis A) and recombinant (e.g. hepatitis B) viruses. Among these, inactivated vaccines are known for their easy production and safety. The present article reviews the literature and patents related to the mechanisms used for viral inactivation, mainly chemical and physical procedures, including the novel strategies that are currently being explored and that have been recently patent protected.

Severe acute respiratory syndrome (SARS) emerged in late 2002 and was controlled in July 2003 by public health measures. Its causative agent, SARS coronavirus (SARS-CoV) jumped from an animal reservoir to humans and has the potential to re-emerge. Following the sequencing of the genetic code and the deciphering of some of the functions of its proteins, including the cellular receptors and host proteins that participate in the life cycle of the virus, promising lead drugs and new uses of old drugs have been discovered. Patent applications for cathepsin L inhibitors have taken new relevance because of the role of cathepsin L in the entry of SARS-CoV into host cells. Likewise, patent applications for SARS-CoV protease inhibitors and interferon and mismatched dsRNA also need to be watched for potential application in treatment and prevention of SARS-CoV. Here, we review the recent advances and inventions that target SARS-CoV infection in humans.

Despite many advances in chemotherapy and other medical techniques, patients with cancer often develop local recurrence or metastatic spread. Recent advances in molecular biology and tumor immunology have led to the design of many new anti-tumor vaccines. Such approaches are now using recombinant viruses to treat different types of cancer. From these new developments, innovative fields are emerging: vaccine virotherapy, viral immunotherapy, oncolytic virotherapy and drug virotherapy. Many viruses are currently exploited as recombinant vectors and each offers natural or synthetic characteristics that may provide unique means to treat cancer. Poxviruses are large double stranded DNA viruses that offer many advantageous characteristics as recombinant vectors. Poxvirus-based vectors offer essentially unlimited possibilities for genetic manipulation due to the large size of their DNA and high degree of safety. Vaccinia virus, the prototype virus of the Orthopoxvirus genus that was extensively used to eradicate Smallpox, and other poxviruses are now being considered and used for the treatment of cancer. This review will cover their utilization as anti-cancer therapeutics by describing recent patents (2000-2005).

Hepatitis C virus (HCV) infection is a leading cause of liver diseases such as cirrhosis and hepatocellular carcinoma. There are estimated 170 million people worldwide chronically infected with the virus. The lack of highly effective and safe therapeutics for HCV infection has spurred intensive efforts to develop anti-HCV drugs as evidenced by the large number of new patent applications filed each year. Nucleoside and nucleotide inhibitors are the analogues of DNA or RNA substrates, and they inhibit viral polymerases by acting as chain terminators, viral mutagens, or simple competitive inhibitors. The successful development of various nucleoside and nucleotide inhibitors for the treatment of HIV and HBV infections has prompted the drug industry to seek similar strategies for HCV. This review summarizes recently issued or published patents covering nucleoside and nucleotide inhibitors for HCV. The claimed chemical structures and available biological activities, mechanism of action, and drug resistance profiles are discussed. The development status of several promising nucleoside inhibitors is also described.

Alternatives to traditional antibiotics and to antiviral and anti-inflammatory drugs are much in need and the molecular design and development of anti-infective compounds constitute a pivotal area in modern medicinal research. Dendrimers are a relatively new class of structurally well-defined, i.e. monodisperse, synthetic polymers with hyperbranched structures which enable a given molecular motif to be presented in a highly multivalent fashion. Several types of dendrimers with various structural elements and molecular dimensions are commercially available at an affordable price. The surface of dendrimers can be modified relatively easily and, depending on the surface motif, the pharmacological properties of the dendrimer such as cytotoxicity, bacteriocidal and virucidal effect, biodistribution and biopermeability may be modulated to fit a specific medicinal purpose. Dendrimers are thus highly suitable tools in drug discovery and they allow the synthesis of molecules with high and specific binding affinities to a wide variety of receptors, viruses and bacteria. Hence the use of dendrimers for the development of antiviral or antibacterial drugs, destroying the infective agent or disrupting multivalent binding interactions between the infective agent and cells of the host organism has become a highly active research field. The wide range of applications reported for the use of dendrimers as anti-infective and anti-inflammatory drugs in the patent literature demonstrates the general applicability of these molecules as drug candidates. The present review will briefly treat the intrinsic properties of dendrimers in biological systems, as well as general concerns regarding the treatment of infective diseases. The use of dendrimers as anti-infective and anti-inflammatory drugs will be based on a thorough review of the recent patent literature.

Several systemic drugs are available for the treatment of moderate-to-severe plaque psoriasis, including photochemotherapy, retinoids, cyclosporin, methotrexate, and fumarates. Although these options have been shown to maintain efficacy, frequently they produce significant subjective side effects. Recently, there has been a significant advance in developing newer medications that may be used for psoriasis. The progress in laboratory techniques has improved our understanding of the immuno-pathogenesis of psoriasis to a point where a number of key cytokines and immune cells - notably tumor necrosis factor-alpha (TNF-α) and T-cells respectively have been identified as critical factors contributing to the immuno-pathogenesis of the disease. Many of these medications are termed "biologic response modifiers" or, more commonly, "biologicals". The latter are a set of different engineered proteins designed to modify defined patho-physiological pathways that regulate pivotal immunological processes such as lymphocytes activation and cytokines production. New strategies and new formulation of biologic therapies, angiogenesis inhibition, immunomodulatory compounds, intracellular messenger targets, are of current interest to dermatologists and medicinal chemists. This review summarizes the current understanding of the immuno-pathogenesis of psoriasis, the mechanism of action and efficacy of current biologic therapies, new patents and their possible future applications in the treatment of psoriasis.